The production of antibodies against self-antigens and/or autoreactive T cells is a hallmark of many autoimmune diseases. Autoantibodies and autoreactive T cells can cause severe tissue damage (e.g., as in lupus nephritis) or loss of blood components (e.g., as in immune thrombocytopenia purpura).
Typically, autoimmune diseases are treated with nonspecific immunosuppressive agents, such as, e.g., cyclophosphamide, methotrexate, azathioprine, and cyclosporine, that impede the immune cells from attacking the organs and tissues. However, immunosuppressive agents are often associated with significant side effects (e.g., toxicity, the undesired suppression of the immune system, etc.).
Due to its immunosuppressive effects, transforming growth factor-beta (TGF-β) has been suggested as a possible therapeutic agent for certain autoimmune diseases, including multiple sclerosis and graft-versus-host disease. Flanders et al., Clin. Med. Res., 1:13-20 (2003). It has also been reported as useful to induce the generation of suppressor T cells in vitro (see, e.g., U.S. Pat. No. 6,759,035). However, TGF-β is a pluripotent cytokine-besides having immunosuppressive properties, it is involved in the extracellular matrix production, and other biological processes. For a review on TGF-β, see, e.g., Cytokine Reference, eds. Oppenheim et al., Academic Press, San Diego, Calif., 2001. Excessive or persistent expression of TGF-β plays a role in organ fibrosis (Kapanci et al., Am. J. Resp. Crit. Care Med., 152:2163-2169 (1995); George et al., Prot. Natl. Acad. Sci., 96:2719-12724 (1999); Kuwahara et al., Circulation, 106:130-135 (2002)), while systemic administration of active TGF-β has been associated with unacceptable toxicity. In particular, in a Phase I/II clinical trial for chronic progressive multiple sclerosis, systemic administration of active TGF-β2 resulted in unacceptable renal toxicity as evidenced by a reduction in glomerular filtration rate. Calabresi et al., Neurology, 51:289-292 (1998). This result has hindered further clinical development of therapies involving systemic administration of active TGF-β. Accordingly, the challenge of selectively harnessing the immunosuppressive potential of TGF-β without incurring its attendant toxicities has remained. In addition, there remains a need to develop methods of treating autoimmune diseases that allow suppression of autoreactive immunity without undesirable side effects.